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21
Cerebrovascular Disease
LISA R. ROGERS
Cerebrovascular disease is an important cause of neu-
rologic morbidity and mortality in patients with can-
cer, and its presence must be considered in any can-
cer patient who experiences cerebral symptoms. It is
the second most common cause of pathologically de-
finable central nervous system (CNS) disease found in
cancer patients at autopsy and is often symptomatic. An
autopsy study from the Memorial Sloan-Kettering Can-
cer Center identified cerebrovascular disease in 500
(14.6%) of 3426 cancer patients at autopsy (Graus et
al., 1985). Of those patients in whom cerebrovascular
disease was identified, 51% had experienced clinical
symptoms related to the disease.
Identifying cerebrovascular disease in the cancer
patient is important because identification and treat-
ment of the disorder can sometimes ameliorate neu-
rologic symptoms and prevent subsequent episodes.
Even when a stroke occurs in the setting of advanced
cancer, treatment can improve the patient’s quality of
life. If a stroke occurs when cancer is limited, failure
to identify and treat the cerebrovascular disease un-
derlying the stroke may doom an otherwise success-
ful outcome of the cancer treatment. In a small per-
centage of patients, stroke is the presenting sign of
cancer, and identification of cerebrovascular disease
in this subset may lead to the diagnosis of cancer.
Identifying cerebrovascular disease in the patient
with cancer presents a challenge to the clinician, as
the pathogenesis is often unique to this group of pa-
tients. In cancer patients, the common risk factors
for stroke, such as systemic and cerebral atheroscle-
rosis, hypertension, and advanced age, are over-
shadowed by the pathophysiologic effects of cancer
454
and its treatment. Coagulation disorders, toxicity of
antineoplastic treatment, and direct effects of cere-
bral tumor are the most common causes of stroke in
this group. Neuroimaging studies are helpful in iden-
tifying the type and location of stroke, but the most
important clues to its etiology in cancer patients are
the type and extent of systemic cancer, the presence
of CNS metastasis, and the type of antineoplastic ther-
apy. This chapter reviews the cerebral hemorrhage
and cerebral infarction syndromes that occur in can-
cer patients, with emphasis on the clinical settings in
which they occur and current methods of diagnosis
and treatment.
CEREBRAL HEMORRHAGE
Pathophysiology and
Clinical Presentation
Table 21–1 lists the etiologies of the most common
cerebral hemorrhage syndromes that occur in cancer
patients. Hemorrhage is usually caused by coagulation
abnormalities, brain metastasis, or a combination of
the two. Hemorrhage typically occurs in the brain pa-
renchyma, but associated intraventricular or sub-
arachnoid hemorrhage may also occur, depending on
the location of the primary hemorrhage. Primary sub-
dural or subarachnoid hemorrhage is uncommon.
Cerebral hemorrhage occurs more often in patients
with leukemia than in those with lymphoma or solid
tumors and is more common in acute than in chronic
leukemias and in myelogenous rather than lymphocytic
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Cerebrovascular Disease 455

Table 21–1. Pathophysiology of Cerebral Hemorrhage in Patients with Cancer

Etiology
Coagulopathy
Disseminated intravascular
coagulation
Thrombocytopenia
Tumor related
Hemorrhage into parenchymal
brain metastases
Ruptured neoplastic aneurysm
Leukostasis, leukemic nodules
Dural metastases
Treatment related
L-asparaginase
Hemolytic uremic-like syndrome
Miscellaneous
Idiopathic thrombocytopenic
purpura, platelet dysfunction,
hyperviscosity, acquired
von Willebrand’s disease
Hypertensive cerebrovascular disease
Pathology
Intraparenchymal hemorrhage
Intraparenchymal hemorrhage
Subdural or subarachnoid hemorrhage
Intraparenchymal hemorrhage
Intraparenchymal and subarachnoid
hemorrhage
Intraparenchymal hemorrhage
Subdural hemorrhage
Intraparenchymal hemorrhage
Intraparenchymal hemorrhage
Intraparenchymal hemorrhage
Intraparenchymal hemorrhage
Tumor Type and Setting
Leukemia, especially early in the course of
promyelocytic leukemia
Leukemia, usually at relapse or the failure
to induce remission
Leukemia, often associated with
disseminated intravascular coagulation
or sepsis
Melanoma, germ cell tumors, lung cancer
Cardiac myxoma, choriocarcinoma, lung
cancer
Leukemia with hyperleukocytosis
Carcinoma, leukemia, lymphoma
Acute lymphocytic leukemia during induction
therapy
Adenocarcinoma treated with chemotherapy,
especially mitomycin C
Lymphoma, multiple myeloma, or chronic
myeloproliferative disorders
Solid tumors

leukemias. The symptoms of intraparenchymal hem-
orrhage may be acute or gradual and include one or
more of the following: headache, vomiting, reduced
level of consciousness, seizures, focal neurologic signs,
and confusion. The symptoms of subdural hematoma
in cancer patients are typically confusion and lethargy,
and these are usually acute. Rarely, there may be focal
neurologic signs (e.g., hemiparesis, hemianopsia,
monoparesis). Subdural hemorrhage is less often fatal
than parenchymal hemorrhage (Graus et al., 1996).
Subarachnoid or intraventricular hemorrhage usually
produces rapid deterioration in the level of con-
sciousness, resulting in coma.
Coagulopathy
In cancer patients, abnormal coagulation that pre-
disposes to cerebral hemorrhage is typically due to
(1) acute disseminated intravascular coagulation
(DIC), (2) the presence of liver metastasis, (3) sep-
sis, and/or (4) thrombocytopenia induced by tumor
invasion of the bone marrow or effects on the bone
marrow of radiation or chemotherapy. Coagulation
disorders are the most frequent cause of cerebral
hemorrhage in patients with leukemia, and hemor-
rhages in these patients are usually symptomatic. In
patients with acute promyelocytic leukemia, a subtype
of acute myelogenous leukemia, DIC is triggered by
release of procoagulant material from the granules in
the progranulocytes. The coagulopathy worsens after
the administration of chemotherapy. Cerebral hem-
orrhage occurs early in the course of this type of leu-
kemia and is often fatal. In contrast, laboratory evi-
dence of DIC is detected in as many as one-third of
patients early in the course of acute lymphoblastic
leukemia, but is rarely associated with clinically sig-
3601_e21_p454-469 2/19/02 9:01 AM Page 456
456 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT
nificant hemorrhage (Higuchi et al., 1998). Dissem-
inated intravascular coagulopathy may become symp-
tomatic in these patients during induction chemo-
therapy, especially in the presence of very low levels
of fibrinogen (Sarris et al., 1996). Cerebral hemor-
rhage is usually a late complication of other types of
leukemia and occurs at relapse or when remission
cannot be induced. In the late stages of those leuke-
mias, the pathogenesis of hemorrhage is multifacto-
rial. Disseminated intravascular coagulopathy may be
present, but is often accompanied by infection, liver
disease, and/or hematologic complications of che-
motherapy.
Primary subdural hemorrhage occurs in leukemia
patients when there is severe and refractory throm-
bocytopenia. In some patients, DIC, sepsis, and
meningeal leukemia are contributing factors to hem-
orrhage (Pitner and Johnson, 1973). Subdural hem-
orrhage is more common in patients with acute myel-
ogenous leukemia after autologous rather than
allogeneic bone marrow transplant (Graus et al.,
1996). An unusual cause of brain hemorrhage is ve-
nous infarction due to cerebral sinus thrombosis as-
sociated with coagulopathy, typically occurring in pa-
tients who have leukemia (Raizer and DeAngelis,
Figure 21–1. Bilateral cerebral hemorrhagic infarctions caused by nonmetastatic superior sagittal sinus thrombosis.
2000). Figure 21–1 shows a postmortem example of
fatal bilateral hemorrhagic infarctions caused by su-
perior sagittal thrombosis in a patient with adeno-
carcinoma and coagulopathy. In patients with solid
tumors, symptomatic parenchymal brain hemorrhage
resulting from coagulopathy is rare and it is usually
a terminal event.
Hemorrhage Associated with
Cerebral Tumor
Hemorrhage into parenchymal metastatic brain tu-
mor is the most common type of brain hemorrhage
in patients with solid tumors. It occurs most fre-
quently in patients with metastatic melanoma, germ
cell tumors (especially choriocarcinoma), and car-
cinoma of the lung or kidney. It is caused by necro-
sis of tumor and the rupture of newly formed blood
vessels or by invasion of blood vessels in the adjacent
brain parenchyma (Kondziolka et al., 1987). In rare
instances, especially with metastasis from malignant
melanoma or choriocarcinoma, the metastasis un-
derlying vascular invasion is microscopic. In more
than one-half of patients, symptoms are acute and may
be the first clinical sign of brain tumor metastasis
3601_e21_p454-469 2/19/02 9:01 AM Page 457
Cerebrovascular Disease
(Lieu et al., 1999). In other patients, the symptoms
are superimposed on chronic or progressive symp-
toms of brain metastasis.
Ruptured neoplastic aneurysms are a rare cause of
intracerebral hemorrhage and predominantly occur in
patients who have cardiac myxoma, lung carcinoma,
or choriocarcinoma (Kalafut et al., 1998). These
aneurysms develop when tumor embolic material in-
vades a cerebral vessel wall. After recanalization, the
damaged wall dilates and ruptures (Murata et al.,
1993). Rarely, aneurysms develop as a result of vas-
cular invasion by a parenchymal metastasis. Neoplas-
tic aneurysms are typically located in distal arterial
branches, usually those of the middle cerebral artery.
Symptomatic subdural hemorrhage associated
with tumor metastasis to the dura is uncommon.
Dural metastasis develops from hematogenous spread
of tumor to the dura or from skull metastasis that in-
vades the dura. Figure 21–2 shows a subdural he-
matoma that was caused by dural metastasis of breast
carcinoma. The subdural hemorrhage may be due to
the rupture of vessels from vascular congestion by
tumor or due to spontaneous hemorrhage of tumor.
In some patients, there may be an effusion from tu-
mor in the dura. The tumors that most commonly un-
derlie subdural hemorrhage associated with dural
metastasis are carcinomas (especially gastric, breast,
or prostate); leukemia and lymphoma are less com-
mon (McKenzie et al., 1990). In some instances, a
superimposed coagulopathy contributes to the hem-
orrhage (Minette and Kimmel, 1989). Signs of sub-
dural hemorrhage usually develop gradually, and
there may be focal neurologic signs in addition to
headache. Epidural hematoma due to dural or skull
metastasis is rare (McIver et al., 2001).
If DIC associated with acute promyelocytic leukemia
is excluded, hyperleukocytosis (peripheral blast cell
count in excess of 100,000/mm3) is the most common
cause of intracerebral hemorrhage at the time of di-
agnosis of leukemia. Hyperleukocytosis occurs most
frequently in patients with acute myelogenous leuke-
mia, especially the monocytic variant (Wurthner et al.,
1999). Patients with hyperleukocytosis experience in-
tracerebral hemorrhage in association with infiltration
of cerebral capillaries by blast cells, but the pathogen-
esis of hemorrhage is controversial. In one series hem-
orrhage occurred while the white blood cell count was
declining following chemotherapy administration
(Wurthner et al., 1999). Postmortem studies reveal
hemorrhage adjacent to dilated and thin-walled vessels
457
that are filled with leukemic blasts (leukostasis) and
adjacent to leukemic nodules (Freireich et al., 1960).
Blast cells have less deformation than red blood cells;
thus hyperviscosity, vascular endothelial damage, and
competition with host cells to produce local hypoxia
might result in hemorrhage.
Leukemic nodules enlarge and invade cerebral
vessels. Leukostasis is more intense in the white mat-
ter, periventricular regions, and leptomeninges than
in the cortex (Nowacki et al., 1995). Intracerebral
hemorrhages associated with hyperleukocytosis are
usually multiple and are located in the white matter.
Intraventricular or subarachnoid hemorrhage may
also occur. In contrast with patients who have hem-
orrhage caused by coagulopathy, only moderate
thrombocytopenia is usually present, which would not
be expected to cause spontaneous hemorrhage. A
rare cause of intraparenchymal hemorrhage is cere-
bral perivascular infiltration of leukemic cells in lep-
tomeningeal leukemia, resulting in the rupture of
cerebral capillaries. Subarachnoid hemorrhage can
also occur in patients with diffuse leptomeningeal tu-
mor when there is thrombocytopenia.
Treatment-Related Hemorrhage
The use of L-asparaginase in induction therapy for
acute lymphocytic leukemia results in cerebral hem-
orrhage or thrombosis in a small percentage of pa-
tients (Urban and Sager, 1981; Gugliotta et al., 1992).
L-asparaginase is known to promote fibrinolysis and
to deplete plasma proteins involved in coagulation,
but the precise mechanism of thrombosis and hem-
orrhage is unknown. In some cases, cerebral hem-
orrhage is due to venous infarction from thrombosis
of the superior sagittal sinus.
A hemolytic uremic–like syndrome is reported in
patients with adenocarcinoma, sometimes develop-
ing after the administration of chemotherapy. The
clinical manifestations are thought to be due to
endothelial damage and include microangiopathic
hemolytic anemia, thrombocytopenia, pulmonary
edema, and renal insufficiency. Similar to the de
novo hemolytic uremic syndrome, the neurologic
signs include headache, confusion, hemiparesis, and
coma. Originally reported as a complication of mit-
omycin C, it has now been associated with several
antineoplastic agents, including bleomycin and cis-
platin (Gordon and Kwaan, 1997). The onset after
chemotherapy administration is highly variable and
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458 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Figure 21–2. Postmortem examination of a subdural hematoma associated with nodular dural metastases (arrow) of breast car-
cinoma.

ranges from days to months. In other cancer patients, Miscellaneous

intracerebral hemorrhage occurs as a terminal event
in the setting of severe thrombocytopenia induced by Hypertension is a rare cause of symptomatic intra-
bone marrow failure from chemotherapy, radiation, cerebral hemorrhage in cancer patients (Graus et al.,
or metastasis. 1985). It occurs primarily in patients with solid tu-
3601_e21_p454-469 2/19/02 9:01 AM Page 459
Cerebrovascular Disease
mors. A high percentage of patients with chronic
myeloproliferative disorders, especially chronic myel-
ogenous leukemia and osteomyelofibrosis, experi-
ence intraparenchymal hemorrhage. Hemorrhage
may coexist with intracerebral thromboses (Buss et
al., 1985), and these tend to occur early in the dis-
ease (Wehmeier et al., 1991). In patients with lym-
phoma, intracerebral hemorrhage may be related to
severe thrombocytopenia from idiopathic thrombo-
cytopenic purpura or to an acquired form of von
Willebrand’s disease. In patients with myeloma, in-
tracerebral hemorrhage may be related to thrombo-
cytopenia and serum hyperviscosity. Primary sub-
arachnoid hemorrhage is sufficiently rare in cancer
patients so that congenital aneurysms should be con-
sidered. Among 24 patients with cancer and primary
subarachnoid hemorrhage in the series by Graus et
al. (1985), 4 had ruptured congenital aneurysms.
Diagnosis
Coagulopathy
The stage of the leukemia and associated clinical fac-
tors such as degree of thrombocytopenia and the pres-
ence of sepsis can suggest the cause of brain hemor-
rhage in patients with leukemia. The diagnosis of
intracerebral hemorrhage is established by MRI or CT
scans of the brain that reveal single or multiple hem-
orrhages. Patients who have acute DIC may also have
systemic thrombosis, including deep vein thrombosis,
pulmonary embolism, or myocardial infarction, and sys-
temic hemorrhage, including hemorrhage in the mu-
cosal surfaces, retinae, skin, genitourinary and gas-
trointestinal tracts, and at the site of venipuncture or
bone marrow aspiration. Laboratory studies to confirm
acute DIC include measurement of platelets, prothrom-
bin time, activated partial thromboplastin time, fibrino-
gen, fibrin split products, fibrinopeptide A, the D-dimer
assay, and the presence of schistocytes on the periph-
eral blood smear. In many patients with cancer, labo-
ratory tests reveal evidence of chronic DIC, but this con-
dition is rarely symptomatic; results of laboratory tests
of coagulation function in all patients must be carefully
interpreted in their clinical context.
Hemorrhage Associated with
Cerebral Tumor
Computed tomography or MRI scans of the brain re-
veal single or multiple hemorrhages when there is
459
hemorrhage into parenchymal brain metastasis. Clues
to intratumoral hemorrhage include a multiplicity of
hemorrhages, brain locations other than those usu-
ally found with hypertensive hemorrhage, and early
edema and enhancement adjacent to the hemorrhage
(Atlas et al., 1987). If an intratumoral brain hemor-
rhage is suspected but the patient is not known to
have cancer, biopsy of the hematoma wall is indicated
to establish the diagnosis. Parenchymal hemorrhages
associated with ruptured neoplastic aneurysms may
be single or multiple. Cerebral angiography in neo-
plastic aneurysms can reveal filling defects, fusiform
and saccular aneurysms, and occluded vessels, but
the sensitivity of angiography is unknown; in some in-
stances, the hematoma obliterates the aneurysm and
angiographic findings are normal.
In patients with subdural hematomas, CT and MRI
brain scans can show acute or chronic subdural fluid
collections. If dural metastasis is present, there may be
evidence of adjacent skull metastasis and dural en-
hancement after injection of a contrast agent such as
gadolinium. However, histologic examination of the
dural membrane or subdural fluid may be necessary
to establish the diagnosis of dural metastasis. Lep-
tomeningeal metastasis is suggested by leptomeningeal
enhancement on neuroimaging studies after injection
of a contrast agent such as gadolinium and proven by
identification of malignant cells in cerebrospinal fluid
or in leptomeningeal biopsy specimens.
Treatment-Related Hemorrhage
Cerebral hemorrhage can occur during or immedi-
ately after induction therapy with L-asparaginase in
patients with acute lymphocytic leukemia. Brain MRI
and magnetic resonance venography can be diagnos-
tic of venous occlusion. Systemic signs of a hemolytic
uremic–like syndrome in conjunction with severe he-
molytic anemia and thrombocytopenia associated
with the administration of chemotherapy for adeno-
carcinoma suggest this diagnosis.
Miscellaneous
Laboratory tests that reveal evidence of extreme
thrombocytosis, impaired platelet function, or hyper-
viscosity can be helpful in identifying the cause of
cerebral hemorrhage in patients with chronic myelo-
proliferative disorders, lymphoma, and multiple
myeloma.
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460 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT
Treatment
Coagulopathy
Successful therapy for acute DIC is multifaceted and
controversial. Evacuation of an intracerebral hemor-
rhage in the setting of coagulopathy is difficult, and in
patients with cancer who have cerebral hemorrhage
caused by DIC treatment should be directed at con-
trolling the systemic tumor and the associated medical
conditions that contribute to the coagulopathy, such as
sepsis. Treatment with heparin and fresh-frozen plasma
can control DIC in some patients. Other therapies in-
clude replacement of clotting factors with blood prod-
ucts such as cryoprecipitate and platelet concentrations
and antifibrinolytic agents. In patients with acute
promyelocytic leukemia and DIC, it is controversial
whether prophylactic heparin as an adjunct to induc-
tion chemotherapy can reduce the incidence of in-
tracerebral hemorrhage. Chemotherapy, however, can
increase the lysis of blast cells and aggravate DIC. All-
trans retinoic acid administered for remission induc-
tion therapy of acute promyelocytic leukemia can dif-
ferentiate abnormal promyelocytes into mature
granulocytes, which improves coagulation function and
results in a slight decrease of early brain hemorrhage
(Tallman et al., 1997). Most patients with subdural he-
matoma caused by coagulopathy can be successfully
managed without surgery (Graus et al., 1996).
Hemorrhage Associated with
Cerebral Tumor
Survival of patients with massive intratumoral par-
enchymal brain hemorrhage or ruptured neoplastic
aneurysms is poor, especially for those who have an
acute onset of symptoms (Graus et al., 1985). These
patients may die as a direct result of the hemorrhage.
In some patients, resection of a single large hema-
toma is life saving (Little et al., 1979). The clinical
course in patients with hemorrhage into brain me-
tastasis who have a stable neurologic condition is no
different from that of patients with nonhemorrhagic
brain metastasis. These patients should receive radi-
ation therapy directed to the underlying brain metas-
tasis. For patients with ruptured neoplastic cerebral
aneurysms, therapy should be directed to the systemic
tumor (appropriate antineoplastic therapy in the case
of systemic cancer and removal of the cardiac tumor
in the case of cardiac myxoma). Brain irradiation is
indicated for neoplastic aneurysms that arise from
systemic carcinoma.
Therapy for subdural hemorrhage associated with
dural metastasis is generally palliative and includes
brain irradiation and drainage of subdural fluid. The
use of antimetabolites and leukapheresis reduces
the frequency of brain hemorrhage in acute leukemia
patients presenting with hyperleukocytosis (Wurthner
et al., 1999).
Treatment-Related Hemorrhage
The chances for neurologic recovery in patients ex-
periencing L-asparaginase–induced thrombosis or
hemorrhage are generally good (Feinberg and Swen-
son, 1988), and cerebrovascular events do not usu-
ally recur after re-treatment. Fresh-frozen plasma may
be beneficial for patients with venous thrombosis, but
it is not known if anticoagulation is necessary. The
prognosis for patients with the hemolytic uremic–like
syndrome induced by chemotherapy is poor, but
steroids and plasma exchange may prolong survival
(Gordon and Kwaan, 1997).
Miscellaneous
Conventional cytoreductive therapy reduces the inci-
dence of cerebral ischemic or hemorrhagic events in
patients with chronic myeloproliferative disorders
(Wehmeier et al., 1991).
CEREBRAL INFARCTION
As is the case with cerebral hemorrhage, the risk fac-
tors for cerebral infarction in patients with cancer are
usually different from those in patients without can-
cer. Table 21–2 lists the causes of cerebral infarc-
tion in cancer patients. Coagulation disorders, infec-
tion, the direct effects of CNS metastasis, and
complications of antineoplastic treatment are the
most common causes. Symptomatic cerebral infarc-
tion is more common in patients who have lymphoma
and carcinoma than it is in those with leukemia, in
whom cerebral hemorrhage predominates.
Two clinical factors make the identification of
cerebral infarction in cancer patients and the deter-
mination of its cause difficult. First, cerebral infarc-
tions in cancer patients are often multifocal, and the
resulting multifocal neurologic signs are difficult to
distinguish from those caused by encephalopathy.
Therefore, the possibility of cerebral infarction must
be considered for all cancer patients who experience
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Cerebrovascular Disease 461

Table 21–2. Pathophysiology of Cerebral Infarction in Patients with Cancer

Etiology Pathology Tumor Type and Setting
Coagulopathy
Nonbacterial thrombotic Cerebral infarction Adenocarcinoma, usually widespread
endocarditis
Cerebral intravascular Cerebral infarction, petechial hemorrhage Lymphoma, leukemia, breast cancer, in
coagulation advanced disease and sepsis
Coagulopathy, etiology Superior sagittal sinus thrombosis with Lymphoma and solid tumors, usually in
undetermined or without adjacent cerebral infarction advanced disease
Infection
Fungal sepsis Cerebral infarction Leukemia
Tumor-related
Skull or dural metastases Saggital sinus thrombosis with or without Lung cancer, neuroblastoma, lymphoma
adjacent cerebral infarction
Tumor embolism Cerebral infarction Lung and cardiac tumors
Leptomeningeal metastasis Cerebral infarction Solid tumors
Radiation-induced vasculopathy Cerebral infarction Head and neck cancer, lymphoma
Chemotherapy Superior sagittal sinus occlusion Leukemia, during induction therapy with
L-asparaginase

Chemotherapy Cerebral infarction Breast cancer during multi-agent

chemotherapy and hormonal therapy;
other solid tumors during cisplatin-based
chemotherapy
Miscellaneous
Atherosclerosis Cerebral infarction Head and neck and lung cancer
Granulomatous angiitis Cerebral infarction Hodgkin’s lymphoma, leukemia
Thrombocytosis Cerebral infarction Chronic myeloproliferative disorders,
particularly essential thrombocytopenia

encephalopathy. Second, proving a link between co-
agulation abnormalities and cerebral infarction can
be difficult because many cancer patients have ab-
normalities of coagulation function that are revealed
by laboratory tests but are not clinically significant.
The most important clues to the etiology of cerebral
infarction are the type of cancer, the extent of sys-
temic metastasis, the presence of CNS metastasis, and
the type of antineoplastic treatment.
Pathophysiology and
Clinical Presentation
Coagulopathy
The majority of patients with advanced solid tumors
have laboratory evidence of clotting activation that is
usually asymptomatic. In a small percentage of pa-
tients, however, the coagulopathy results in throm-
bosis of arteries or veins in the systemic or cerebral
circulation. There are multiple risk factors for coag-
ulopathy and thrombosis, including a complex inter-
action between tumor cells and their products with
host cells, cancer treatment including single- or mul-
tiple-agent chemotherapy, hormonal therapy, and he-
matopoietic growth factors. Nonbacterial thrombotic
endocarditis is the result of a hypercoagulable state
and is characterized by the development of sterile
platelet-fibrin vegetations on cardiac valves.
Nonbacterial thrombotic endocarditis is the most
common cause of symptomatic cerebral infarction
in cancer patients (Graus et al., 1985). Figure 21–3
shows cardiac nonbacterial thrombotic endocarditis
in a patient with lung adenocarcinoma. Patients with
cerebral infarction caused by nonbacterial throm-
botic endocarditis usually experience focal neuro-
logic signs, and angiography in these patients typi-
cally shows multiple branch occlusions of the middle
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462 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Figure 21–3. Postmortem examination demonstrating vegetations of nonbacterial thrombotic endocarditis attached to all cusps
of the aortic valve. (The valve has been opened anteriorly.) The arrow indicates one area of vegetation.

cerebral artery. Focal signs may be preceded by tran-
sient ischemic attacks. Some patients also develop en-
cephalopathy because of multifocal infarctions. Post-
mortem studies suggest that cerebral infarctions are
caused by embolization of cardiac vegetations to the
brain, cerebral intravascular thromboses that result
from the associated coagulation disorder, or both
(Reagan and Okazaki, 1974; Rogers et al., 1987).
Nonbacterial thrombotic endocarditis occurs most
commonly in patients with adenocarcinoma, espe-
cially mucin-producing carcinomas of the lung or
gastrointestinal tract. It usually develops in patients
with advanced cancer, but can occur in patients with
early-stage cancer and can even be the presenting sign
of cancer (Rogers et al., 1987). Evidence of systemic
thrombosis or hemorrhage suggests the presence of
nonbacterial thrombotic endocarditis.
Cerebral intravascular coagulation is due to throm-
botic occlusion of small cerebral vessels caused by a
coagulopathy unaccompanied by nonbacterial throm-
botic endocarditis. It is the second most common cause
of symptomatic cerebral infarction in patients with can-
cer (Graus et al., 1985). Patients with cerebral in-
travascular coagulation develop encephalopathy, and
approximately one-half of patients have superimposed,
sometimes transient, focal neurologic signs (Collins et
al., 1975). The clinical course is progressive. Typically,
multiple vessels in more than one major vessel territory
of the brain and leptomeninges—usually small arter-
ies, arterioles, capillaries, or venules—are occluded
with fibrin. Figure 21–4 shows fibrin occlusions of lep-
tomeningeal vessels in association with cerebral infarc-
tions in a patient with breast cancer and cerebral
intravascular coagulation. Cerebral intravascular coag-
ulation is reported in patients with leukemia, breast can-
cer, and lymphoma, usually in the setting of advanced
disease and sepsis. Amico et al. (1989) reported sys-
temic and cerebral infarctions in six patients with mu-
cinous cancers. At autopsy, mucin was present within
vessels, macrophages, and areas of infarction. It is
unknown whether mucin deposition results from me-
tastasis or is associated with a cancer-related coagu-
lopathy.
Nonmetastatic occlusion of large cerebral venous
structures in cancer patients is caused by a coagula-
tion disorder associated with cancer or with chemo-
therapy. The most common cerebral venous structure
affected is the superior sagittal sinus, and the under-
lying tumor is usually leukemia (Raizer and DeAnge-
lis, 2000). The incidence of this disorder is unknown
3601_e21_p454-469 2/19/02 9:01 AM Page 463
Cerebrovascular Disease
Figure 21–4. Organizing fibrin thrombi (arrows) in small leptomeningeal arteries overlying an area of cerebral infarction in a patient
with disseminated breast carcinoma and cerebral intravascular coagulation. Hematoxylin and eosin; original magnification, 50.
because the sinus occlusion can recanalize and is,
therefore, underreported in autopsy series. The on-
set of symptoms from nonmetastatic superior sagittal
sinus thrombosis is typically sudden headache;
seizures, focal neurologic signs, or encephalopathy
develop if there is brain hemorrhage or infarction.
Superior sagittal sinus occlusion is associated with in-
duction therapy that includes the administration of
L-asparaginase to patients with acute lymphocytic leu-
kemia (see “Treatment-Related Cerebral Infarction”
in this chapter). In other patients with lymphoma or
solid tumors, it usually occurs in the setting of wide-
spread systemic metastatic disease.
Infarction Associated with
Cerebral Infection
Cancer patients are predisposed to systemic infections
because of immunosuppression caused by the tumor
or by treatment with radiation, chemotherapy, broad-
spectrum antibiotics, or immunosuppressants. Cere-
bral infarction associated with infection is most com-
monly caused by fungal septic emboli, typically of
Aspergillus and Candida species. Fungal sepsis oc-
curs more commonly in patients with leukemia than
463
in those with lymphoma or carcinoma. Common sites
of entry are the lower respiratory tract for Aspergillus
and the gastrointestinal or genitourinary tracts or in-
dwelling venous catheters for Candida species. Cere-
bral infarctions associated with cerebral infection are
often multiple and may be hemorrhagic (Walsh et
al., 1985). The neurologic signs usually consist of
seizures, focal cerebral signs, or encephalopathy.
Acute focal signs and seizures are more common in
patients with Aspergillus infection, and encephalopa-
thy is more common in patients with Candida infec-
tion. Meningitis is rarely present.
Infarction Associated with Cerebral Tumor
Skull or dural tumor that infiltrates or compresses
the superior sagittal sinus can produce venous stasis
and thrombosis. In contrast to patients with non-
metastatic superior sagittal sinus thrombosis, patients
with the metastatic type of thrombosis develop suba-
cute symptoms resulting from increased intracranial
pressure (typically headache, vomiting, and pa-
pilledema). Focal neurologic signs or encephalopa-
thy may be present if there is cerebral infarction. It
occurs most commonly in patients with neuroblas-
3601_e21_p454-469 2/19/02 9:01 AM Page 464
464 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT
toma, lung cancer, and lymphoma, but is reported in
a variety of tumors.
Another mechanism for tumor-related cerebral in-
farction is embolism of a tumor fragment to the brain.
This can produce focal or multifocal cerebral signs,
sometimes preceded by transient ischemic attacks
(O’Neill et al., 1987). Embolism of a tumor fragment
to the brain is reported exclusively in patients with
solid tumors, usually those with a primary or meta-
static cardiac or lung tumor that is the source of the
embolus. Cerebral embolism can occur at the time of
manipulation of the lung in patients with lung tumor
undergoing thoracotomy (Lefkovitz et al., 1986;
O’Neill et al., 1987). It can be the presenting sign of
cardiac tumor, especially cardiac myxoma. Lep-
tomeningeal metastasis is a rare cause of cerebral in-
farction. Infarction may be the sole manifestation of
this disorder, or there may be accompanying typical
signs, including headache, cranial nerve palsies, and
radiculopathies. Postmortem studies suggest that in-
farction occurs because tumor infiltrates the cerebral
arteries in the Virchow-Robin spaces and causes vas-
cular occlusion or spasm (Klein et al., 1989). The in-
farctions may be multifocal.
Treatment-Related Infarction
Neck radiation administered for head and neck can-
cer or lymphoma can produce delayed extracranial
carotid stenosis or occlusion. In a prospective study
of carotid duplex ultrasound performed in 240 pa-
tients with head and neck cancer who received ra-
diation to the cervical region, a greater than 70%
stenosis of the common and/or internal carotid
artery was detected in 28 patients (11.7%) (Cheng
et al., 1999). Histologic examination of the diseased
artery suggests that radiation produces or acceler-
ates atherosclerosis. Patients may develop transient
ischemic attacks, including amaurosis fugax, or
cerebral infarction. Murros and Toole (1989) re-
ported a wide interval between radiation therapy and
the development of this complication, with a mean
interval of 19 years. Carotid artery rupture is a po-
tentially fatal complication of head and neck tumor
resection and neck irradiation. It is usually associ-
ated with orocutaneous fistulas, necrosis of the skin
flap, and infection (McCready et al., 1983). Patients
may die from exsanguination. If the carotid rupture
is detected and the artery is ligated, there is a sig-
nificant chance of cerebral infarction and death
(Razack and Sako, 1982).
Potential mechanisms for abnormal coagulation
function in patients receiving chemotherapy include
alterations in coagulation factors or anticoagulant
proteins and endothelial damage produced by these
agents. Because of the small number of events oc-
curring in individual treatment studies and the lack
of uniform reporting of thromboembolism, including
stroke, the evidence for a causal relationship with an-
tineoplastic agents, regardless of other risk factors,
is weak (Lee and Levine, 1999). The best-recognized
cerebrovascular complication of chemotherapy is ve-
nous thrombosis caused by L-asparaginase used in
combination induction chemotherapy for patients
with acute lymphocytic leukemia (Lee and Levine,
1999; Gugliotta et al., 1992). L-asparaginase pro-
motes fibrinolysis and causes a depletion of plasma
proteins involved in coagulation. There may be pro-
motion of thrombosis by a transient increase in un-
usually large plasma von Willebrand’s factor multi-
mers (Pui et al., 1987). There are also uncommon
reports of systemic and cerebral venous and arterial
thromboembolic complications in women with breast
cancer receiving multiagent chemotherapy (Wall et
al., 1989), especially when chemotherapy is com-
bined with hormonal therapy (Saphner et al., 1991).
Complications usually occur early in treatment.
A rare neurologic complication of chemotherapy
is cerebral embolization from a ventricular mural
thrombus that forms in association with cardiomy-
opathy resulting from chemotherapy with doxoru-
bicin (Adriamycin) (Schachter and Freeman, 1982).
Transient focal neurologic signs suggesting transient
ischemic attacks can occur during interleukin-2 ther-
apy (Bernard et al., 1990).
Miscellaneous
Atherosclerosis is the most common cause of cere-
bral infarction found at autopsy in patients with can-
cer, but it accounts for only 14% of symptomatic in-
farctions (Graus et al., 1985). The most common
tumors associated with symptomatic cerebral infarc-
tion from atherosclerosis are head and neck cancers
and lung cancer. A less common cause of sympto-
matic cerebral infarction is granulomatous angiitis
occurring in patients with Hodgkin’s disease or leu-
kemia (Inwards et al., 1991; Lowe and Russell,
1987). Signs include headache, fever, confusion,
seizures, obtundation, or hemiparesis. Patients with
chronic myeloproliferative disorders who have ex-
treme thrombocytosis can experience cerebral arte-
3601_e21_p454-469 2/19/02 9:01 AM Page 465
Cerebrovascular Disease
rial or venous thromboembolic events (Randi et al.,
1998). These complications are most common in pa-
tients with polycythemia vera and essential thrombo-
cythemia and occur more often in older patients
(Jabaily et al., 1983; Wehmeier et al., 1991). Platelet
thromboembolism is likely caused by inherent alter-
ations of platelet function in addition to the exces-
sively high number of platelets. Neurologic symptoms
are most common before and shortly after the diag-
nosis of chronic myeloproliferative disorders, prob-
ably because cytoreductive therapy administered af-
ter the diagnosis is effective (Michiels et al., 1993).
In patients with essential thrombocythemia, symp-
toms are usually transient and are poorly localized;
they include unsteadiness, dysarthria, and scotomas.
Focal symptoms such as transient monocular blind-
ness or limb weakness are less common. They are of
sudden onset and are often accompanied by head-
ache. Systemic arterial or venous thrombosis may also
occur. Patients with Hodgkin’s disease who are in re-
mission or cured can experience episodic neurologic
dysfunction that resembles transient ischemic attacks
(Feldmann and Posner, 1986). The cause of these
symptoms is unknown.
Diagnosis
Coagulopathy
Patients with stroke caused by coagulation disorders
may have evidence of systemic thrombosis or
hemorrhage. Particularly, patients with nonbacterial
thrombotic endocarditis may have systemic bleeding,
limb thrombophlebitis arterial occlusion, pulmonary
embolism, or myocardial infarction (Reagan and
Okazaki, 1974; Rogers et al., 1987). Laboratory tests
may reveal evidence of DIC in some patients (Rogers
et al., 1987), but in many patients abnormalities on
coagulation function tests are indistinguishable from
the abnormalities commonly associated with cancer.
These abnormalities include markers of clotting ac-
tivation, such as abnormal thrombin–antithrombin
complex, prothrombin fragment F 1  2, and D-
dimer.
Cardiac murmurs are rare, and transthoracic echo-
cardiography is usually nondiagnostic because of the
small size of the cardiac vegetations. Transesophageal
echocardiography can be diagnostic (Blanchard et
al., 1992). Computed tomography or MRI scans of
the brain may reveal cerebral infarction. In patients
who experience focal neurologic signs, cerebral an-
465
giography is a sensitive test for the diagnosis of cere-
bral infarction from nonbacterial thrombotic endo-
carditis. In these patients, cerebral angiography typ-
ically shows multiple branch occlusions of the middle
cerebral artery (Rogers et al., 1987). Many patients
with cerebral intravascular coagulation have systemic
bleeding, but results of laboratory tests of coagula-
tion function are nonspecific. In a study by Collins et
al. (1975), neuroimaging studies performed in a
small number of patients were normal. There is no
method currently known to diagnose this syndrome
aside from postmortem examination.
Magnetic resonance imaging of the brain is the
imaging procedure of choice to detect superior sagit-
tal sinus thrombosis caused by coagulopathy. It can
document the lack of normal flow void within the oc-
cluded sinus and can reveal enlarged collateral veins
(Sze et al., 1988). Adjacent cerebral hemorrhage or
infarction can also be visualized. When MRI is non-
diagnostic, magnetic resonance venography can be
diagnostic (Fig. 21–5).
Infarction Associated with Infection
Computed tomography and MRI brain scans can re-
veal infarctions in patients with septic cerebral em-
bolism. Focal enhancement may appear later if the
infarctions evolve into abscesses. Cerebrospinal fluid
examination is generally nondiagnostic because usu-
ally only mild pleocytosis and protein elevation are
present. Cultures are typically negative. Hemorrhagic
cerebrospinal fluid can be a clue to Aspergillus in-
fection (Walsh et al., 1985). Blood cultures are of-
ten negative, but clinical or radiographic evidence of
pulmonary infection suggests systemic Aspergillus in-
fection. Aspergillus can be isolated from respiratory
secretions or open lung biopsy specimens, but open
lung biopsy is potentially hazardous in many cancer
patients because of coexisting thrombocytopenia
(Walsh et al., 1985).
Infarction Associated with Cerebral Tumor
Brain MRI and magnetic resonance venography are
the methods of choice to diagnose metastatic supe-
rior sagittal sinus occlusion and to reveal associated
cerebral infarction. In patients with superior sagittal
sinus occlusion due to skull or dural tumor, MRI may
also reveal evidence of adjacent skull or dural me-
tastasis. Dural or leptomeningeal metastasis will usu-
3601_e21_p454-469 2/19/02 9:01 AM Page 466
466 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT
Figure 21–5. Nonmetastatic superior sagittal sinus occlusion (arrowhead) visible on two-dimensional time-of-flight magnetic res-
onance venogram.
ally enhance after injection of gadolinium. In patients
with tumor embolic infarctions, the infarctions can
be seen on CT or MRI scans, and angiography may
reveal vascular occlusions (Marazuela et al., 1989;
O’Neill et al., 1987); however, these findings are not
specific, and a definitive diagnosis of tumor embolism
can be established only if there is a simultaneous pe-
ripheral arterial embolism that can be examined his-
tologically. Patients in whom tumor embolic infarc-
tion is suspected should undergo serial CT or MRI
brain scans for evaluation of growth of the brain me-
tastasis. Clinical clues to the presence of primary or
metastatic cardiac tumor include a new onset of con-
gestive heart failure, pericardial effusion, rapid car-
diac enlargement, or arrhythmias that are difficult to
control. Echocardiography is diagnostic.
Treatment-Related Infarction
Carotid angiography in patients with radiation-in-
duced carotid artery disease usually reveals occlusion
or extensive stenosis of the common carotid artery
that is confined to the field of irradiation. The length
of stenosis in these patients is typically greater than
it is in patients with atherosclerosis not associated
with irradiation (Fig. 21–6). Little information is
available on neuroimaging abnormalities in patients
who experience cerebral infarction related to che-
motherapy administration except for patients with su-
perior sagittal sinus occlusion. There are no labora-
tory tests that can diagnose chemotherapy-induced
coagulation abnormalities.
Miscellaneous
Atherosclerotic brain infarction is suggested by the
patient’s age and the presence of typical risk factors
for atherosclerosis. Granulomatous angiitis is sug-
gested by the presence of cerebral infarctions, hem-
orrhages, or contrast-enhancing masses on CT or MRI
brain scans in patients with lymphoma or leukemia.
Angiography may show a classic beading pattern but
3601_e21_p454-469 2/19/02 9:01 AM Page 467
Cerebrovascular Disease
Figure 21–6. Cerebral angiography in a patient with laryn-
geal cancer and radiation-induced carotid atherosclerosis re-
veals irregularity and moderate stenosis of the distal left com-
mon carotid artery. There is a long segment of diffuse
irregularity and severe stenosis alternating with zones of di-
latation in the proximal internal and external carotid arteries.
The area of involvement of the common, internal, and exter-
nal carotid arteries corresponds to the field of radiation.
may be nonspecifically abnormal or normal. The most
definitive method for diagnosis of granulomatous
angiitis is biopsy, but its sensitivity is low (Inwards et
al., 1991). The association of cerebral infarction with
thrombocythemia can be determined by measuring
the platelet count.
467
Treatment
Coagulopathy
Effective therapy for coagulation disorders must be
directed to the underlying tumor, to associated med-
ical conditions such as sepsis that predispose the pa-
tient to the disorder, and to the coagulation disorder
itself. Management decisions for coagulopathy are
still controversial, and therapy must be individualized.
Low-molecular-weight heparin or low-dose warfarin
can reduce the risk of systemic venous thromboem-
bolism in cancer patients (Levine and Lee, 2001), but
their role in the prophylaxis of stroke is unknown. Pa-
tients who experience cerebral infarction from non-
bacterial thrombotic endocarditis may benefit from
anticoagulation therapy. In the series by Rogers et al.
(1987), heparin therapy was effective in reducing
ischemic symptoms in some patients with cerebral in-
farction, and the incidence of hemorrhagic infarction
and cerebral hemorrhage, possible side effects of this
therapy, was no greater than in patients who were not
anticoagulated. However, anticoagulation must be un-
dertaken judiciously because of the risk of systemic
and cerebral hemorrhage in patients with this disor-
der. Appropriate therapy for cerebral intravascular
coagulation is not known. Heparin and urokinase are
reported to be beneficial in reducing the morbidity of
superior sagittal sinus thrombosis in patients without
cancer (Einhaupl et al., 1991; De Bruijn and Stam,
1999; Philips et al., 1999), but no prospective stud-
ies have been performed in patients with cancer.
Infarction Associated with Infection
Patients with fungal septic cerebral infarction should
be treated with antifungal therapy, but the prognosis
for recovery and survival is poor (Walsh et al., 1985).
Infarction Associated with Cerebral Tumor
Patients with metastatic superior sagittal sinus occlu-
sion should be treated with irradiation of the brain.
It is not known whether anticoagulation therapy is ef-
fective in treating this disorder. In patients with em-
bolic infarction from malignant tumors, the brain
should also be irradiated. In those patients with car-
diac tumors, removal of the cardiac tumor will
prevent subsequent embolization. Patients with lep-
tomeningeal metastasis should be treated with radia-
tion to the symptomatic areas of the neuraxis and with
systemic or intraventricular chemotherapy.
3601_e21_p454-469 2/19/02 9:01 AM Page 468
468 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT
Treatment-Related Infarction
Patients with symptomatic or high-grade radiation-in-
duced carotid stenosis can be effectively treated with
endarterectomy; the long-term patency rates are sim-
ilar to those in nonirradiated patients (Kashyup et al.,
1999). Endovascular occlusion is a safe and effective
method to avoid carotid artery ligation and prevent
cerebral infarction in patients with carotid artery rup-
ture (Citardi et al., 1995). If carotid ligation is re-
quired, low-dose heparin may reduce the risk of cere-
bral infarction (Leikensohn et al., 1978). There is no
effective therapy known for the vascular complica-
tions of chemotherapy, although Feinberg and Swen-
son (1988) suggest that prophylactic fresh-frozen
plasma be administered to patients receiving L-as-
paraginase. In other situations, the benefits of che-
motherapy must be carefully weighed against the risk
of recurrent thromboembolic events.
Miscellaneous
Granulomatous angiitis can respond to treatment di-
rected to the underlying cancer (Hodgkin’s disease
or leukemia) or to steroids and cytotoxic drugs ad-
ministered for vasculitis (Inwards et al., 1991). As-
pirin and cytostatic reduction of the platelet count are
effective in preventing recurrence of thrombotic
events in patients with essential thrombocythemia
(Michiels et al., 1993). The clinical course of patients
with Hodgkin’s disease who experience transient neu-
rologic symptoms of unknown etiology is benign, and
no treatment is indicated (Feldmann and Posner,
1986).
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